Theories Of Atherogenesis Research Articles

Inflammation as a universal pathogenetic link between injury, repair and regeneration, in acute coronary syndrome. From experiment to clinic

Theory of atherogenesis and its complications underwent numerous changes. Today we observe that inflammation is a universal pathogenetic link between various processes such as atherosclerosis, rupture of atherosclerotic plaques and following myocardial infarction, post-infarction cardiac repair and heart failure. This review discusses examples, difficulties, and prospects of implementation of anti-inflammatory therapies in management of acute coronary syndrome and its complications.

Replacing Magic Bullets With Beneficial Pleiotropy in Atherosclerosis

Atherosclerosis is a complex process, involving the interaction of multiple cell types and processes. The next generation of therapeutics needs to focus on pathways exerting multiple beneficial effects on multiple processes in multiple cell types. Theories of atherogenesis have evolved over the decades, with established concepts often being incorporated into new theories. This is the natural progression of science; the old theories are not necessarily discredited—in many cases, they explained what was known at the time—but rather new models emerge that incorporate new knowledge and change the emphasis placed on particular processes. Thus, “Time obliterates the fictions of opinion and confirms the decisions of nature” (Marcus Tullius Cicero). Each model is presented as the state of the art, and each is embraced by a new generation of opinion leaders. What has not changed, however, is the hope that each new theory of atherogenesis will result in a new magic bullet, a pharmacological ideal of a drug able to selectively target a disease without other effects on the body, originally defined by Paul Ehrlich for a drug for antibacterial therapy. Individual cell types, processes, and molecules have been sequentially implicated in theories of atherogenesis, such that the whole process can become viewed as driven by their dysfunction, and thus become targets for magic bullets. For example, endothelial cells, smooth muscle cells, macrophages, T-lymphocytes, bone marrow–derived stem cells, or endogenous vessel wall–derived stem cells; processes such as lipid insudation, inflammation, cell proliferation, cell migration, cell death, or matrix breakdown; or the latest gene implicated by basic science or genome-wide association studies have all been presented as fundamental and necessary to atherosclerosis. As researchers, we test the validity of this concept for each cell type, process or molecule by increasing or decreasing its abundance, activity or expression, and determine whether it increases or …

Syndrom-Pathogen Effect of Ozone Therapy and Nauheim Baths on Patients with Cardiovascular Disease

Despite different theories of atherogenesis, pathogenesis of this disease is, foremost, associated with the lipid storage disease, blood rheological properties, lipid peroxidation. Microcirculation disorders have significant role for pathogenesis of many illnesses, primarily, cardiovascular. Among possible reasons of increased risk of their pathway are the increase in the activity of sympathetic neurovegetative system, psychoemotional tension emergion. Application of gas therapy methods, such as ozone therapy and carbon dioxide in the form of Nauheim baths is one of the prospect trends in preventive treatment. The obtained results of these methods application in the course of resort treatment showed positive dynamics for homeostasis indicants. They can serve as an indication for the use of carbon dioxide and, especially, ozone therapy for

Methylation profiling of DNA in the area of atherosclerotic plaque in humans

Mutation theory of atherogenesis proved by “loss of heterozygosity” and microsatellite instability in the area of atherosclerotic plaques is complemented by data on epigenetic variability of genetic loci involved in the pathologic process. However, only recently large-scale analysis of epigenetic modifications in the human genome became possible. For the first time, the quantitative microarray-based methylation profiling of 1505 CpG-sites in 807 genes was performed in atherosclerotic plaques of aorta and carotid artery from humans using the GoldenGate Methylation Cancer Panel I (Illumina, United States). One hundred and three (7%) CpG-sites in 90 (11%) genes were differentially methylated between tissue samples. The most pronounced differences in DNA methylation levels were registered for a site located in CpG-island of the imprinted gene H19. By comparing 90 genes that were differentially methylated between tissue samples in our study, 10 genes (ICAM1, GSTM1, IGFBP1, POMC, APOA1, IL1RN, INS, LTA, MMP3, THBS2) were overlapped with data in the Human Genome Epidemiology Network (HuGENet), in which they were identified as candidates for cardiovascular disease continuum.

Dietary factors in atherogenesis.

Emerging evidence continues to increase our awareness of the complexity of pathologic processes involved in atherogenesis. Dietary modulation exclusively targeting cholesterol consumption is rapidly becoming an archaic mode of intervention as alternative theories of atherogenesis evolve. The interaction of nutrients that occurs with different dietary patterns has been the subject of intense research. Similarly, the effect of diet on vascular reactivity, lipid metabolic kinetics, and antioxidant potential has enormous implications for therapeutic modalities targeting atherosclerosis. Many dietary strategies aimed at inhibiting and preventing atherogenesis have resulted from ongoing research. Consensus opinions extrapolated from available data have also emerged. Regardless, the precise role of dietary modulation in atherogenesis is yet to be fully elucidated. This article reviews recent evidence relating to the interface between dietary factors and biologic models of atherogenesis. Clinical implications and practical applications are also discussed.

The genesis of atherosclerosis and risk factors: a review.

Atherosclerosis constitutes the most common medical and surgical problem. This can be manifested clinically as stroke, coronary artery disease, or peripheral vascular disease. In the present review the microscopic appearance of the normal arterial wall, the definition of atherosclerosis and the five theories of atherogenesis are described. These are: the lipid theory, the hemodynamic theory, the fibrin incrustation theory, the nonspecific mesenchymal hypothesis and the response to injury hypothesis. Based on the above theories the sequence of events in atherogenesis is analyzed. The classification of the atherosclerotic lesions according to Stary (types I-VI) and their characteristics appear in a table. The epidemiology and the role of the following risk factors are presented in detail: age, sex, lipid abnormalities, cigarette smoking, hypertension, diabetes mellitus, physical inactivity, alcohol consumption, obesity, and hemostatic factors. In addition, less common genetically determined associations like homocystinuria, Tangier disease, Hutchinson-Gilford syndrome (progeria), Werner's syndrome, radiation induced atherosclerosis and the implications of Chlamydia pneumoniae on the arterial wall are discussed.

人体病理の立場からの検証

人体病理の立場からの検証

Novel cell culture medium for use in oxidation experiments provides insights into mechanisms of endothelial cell-mediated oxidation of LDL.

Though one prominent theory of atherogenesis involves free-radical oxidation of low-density lipoprotein (LDL) within the vessel wall by one of the vascular cell types, the mechanism for cell-mediated LDL oxidation remains unclear[sn1]. In these studies we examined the effects of media phenols, thiols, and metals on endothelial cell-mediated oxidation. We found that cell culture media such as Dulbecco modified Eagle medium and minimal essential medium are unable to support cell-mediated oxidation of LDL because they contain high concentrations of phenol red (PR) and tyrosine, both of which strongly inhibit cell-mediated oxidation. Ham's F-10, a commonly used medium for cell-mediated oxidation experiments, is also not entirely appropriate, as it contains both PR and cysteine. Cysteine is not critical for endothelial cell-mediated oxidation, but does increase oxidation of LDL in the absence of cells. Finally, of utmost importance to cell-mediated oxidation was the presence of either micromolar concentrations of Fe(II) or physiological concentrations of holo-ceruloplasmin, the protein which carries copper in plasma. An appropriate culture medium for use in cell-mediated oxidation experiments should thus contain either micromolar concentrations of Fe(II) or physiological concentrations of holo-ceruloplasmin, and should be prepared without PR, cysteine, or large concentrations of tyrosine, all of which are shown here to inhibit endothelial cell-mediated LDL oxidation. These results are consistent with a mechanism of cell-mediated oxidation involving Fenton-type chemistry and redox cycling of the metal.

Oxidized LDL and atherogenesis: relation to risk factors for coronary heart disease.

According to a new theory, a critical step in atherogenesis is oxidation of low-density lipoprotein (LDL) within the arterial wall. Direct data supporting this theory are limited, but indirect evidence suggests that oxidized LDL plays a role in atherogenesis. An important question is whether the LDL-oxidation hypothesis conforms to what is known about other risk factors for coronary heart disease (CHD), such as hypertension, smoking, low high-density lipoprotein (HDL) levels, and diabetes mellitus. Perhaps a unified theory of atherogenesis could be formulated if these risk factors exert their atherogenic actions in part by promoting, facilitating, or permitting the oxidation of LDL.

Patterns of Internal Elastic Lamina Morphology in the Canine Common Carotid Artery

The internal elastic lamina (IEL) of normal canine carotid arteries was examined by scanning electron microscopy in pressure-fixed specimens with intact endothelium. IEL appearance showed a marked variation between animals and was classified into fenestrated sheet, fibrous, and mixed varieties. This interpretation of the apparent morphology was confirmed with transmission electron microscopy. It was clear that IEL fenestrae were associated with surface depressions and that in areas of fibrous IEL there was surface elevation over individual fibres. Within individual animals there was little variation in the pattern of IEL either along or between common carotid arteries. If theories of atherogenesis involving the IEL are correct, the variation of IEL patterns between animals would suggest a corresponding variation of incidence and severity of atheromatous lesions of the common carotid artery between animals. Further, the occurrence of fibrous areas distributed throughout the fenestrated sheet would suggest a focal distribution of lesions along such arteries.

Putative atherogenic factors in patients with chronic renal failure

HIS review analyzes several factors which may initiate and sustain atherosclerosis in patients with chronic renal failure. These factors are examined within the framework of the “injury” theory of atherogenesis, which postulates that repeated cycles of endothelial cell injury, platelet deposition, and smooth muscle cell proliferation lead to the formation of typical atherosclerotic plaques. Thus, in the patient with chronic renal failure, endothelial cell damage may be due to hypertension, immunologic injury, or cigarette smoking. Platelet adherence to the damaged vessel wall may be facilitated by the increased levels of the factor VIII/van Willebrand factor found in these patients. Platelets activated during hemodialysis can release growth factors which stimulate vascular smooth muscle cell proliferation. Discrete areas of proliferating smooth muscle cells may preferentially incorporate cholesterol, which then accumulates in the tissues because the transfer of tissue cholesterol to plasma is impaired as a result of reduced or abnormal plasma high density lipoprotein. Ultimately, intimal thickening may occlude the vessel lumen, producing end-organ damage. As the treatment of chronic renal failure enters upon another decade of continued progress and the life span of affected patients lengthens, atherosclerosis and its complications are emerging as significant problems in these patients. In 1974, Lindner et al’ reported a mortality rate of 56 percent in a group of 39 patients with chronic renal failure treated by maintenance hemodialysis. These patients had a mean age of 37 years and were initially free of vascular or other systemic disease. Careful follow-up over a 13-year period disclosed that 14 (16 percent) of the deaths were due to complications of atherosclerosis; coronary heart disease was confirmed by necropsy in most cases. The mortality rates for this group were five times those seen in age matched subjects with hypertension, and were similar to those noted in familial hypercholesterolemia.’ The data suggest that atherosclerosis develops often and progresses with great rapidity in these individuals. Studies of larger numbers of patients have confirmed the high rate of complications due to cardiovascular disease.3*4 There is disagreement, however, as to whether this “accelerated atherosclerosis” is due to dialysis per se or is explainable by the high prevalence of major risk factors in these patients. 5-g Nicholls et al” presented evidence that the disease is already established in these patients when they come to dialysis. They observed that the morbidity and mortality due to atherosclerosis was most prominent in newly recognized patients with chronic renal failure, and that the incidence of new atheromatous disease did not increase during dialysis. Nevertheless, 9 of their 32 patients who died and were autopsied had severe occlusive arterial disease, and the average age of these patients was only 47 years. In another series,’ the de novo incidence of ischemic heart disease in 382 patients on chronic hemodialysis was 10.2%. In this review, we will examine several factors

“Spontaneous” endothelial injury in the rat caudal artery

Numerous spontaneous lesions, characterized principally by a gap in the internal elastic lamina, form with age in the caudal artery of the young, male Wistar rat. Such newly formed lesions were studied, with special reference to the state of the endothelium, using three techniques: “en face” examination of silver-stained caudal artery, [ 3H]thymidine autoradiography, and light and electron microscopy. In many, but perhaps not all cases, areas of endothelium are damaged or removed either simultaneously or shortly after the formation of the break in the internal elastic lamina and some underlying smooth muscle cells are damaged. Polymorphonuclear cells and monocytes are attracted to the site of injury. A repair process rapidly ensues including rapid regeneration of the endothelium and proliferation of smooth muscle cells in the underlying media and of some adventitial fibroblasts. This process results in the restitution of the endothelial monolayer and the laying down of one or several layers of longitudinal smooth muscle and collagen and elastic fibers in the subendothelial space. This demonstration of naturally occurring damage to fairly large areas of endothelium and the events which occur in the repair process is of interest in view of the “response-to-injury” theory of atherogenesis; observations are discussed in the light of previous studies performed on experimentally removed endothelium.

Hypercholesterolemia and platelets.

Many lines of evidence have linked the circulating plasma lipoproteins with thrombosis, and both with atherosclerosis. Many theories of atherogenesis include mural thrombosis as one of the inciting factors, or the sole inciting factor, for atherosclerotic plaque formation. Clinically, elevated plasma lipids and increased concentrations of circulating lipoproteins have been known for years to predispose to early and severe atherosclerosis and its thrombotic complications. Familial hypercholesterolemia (Type II hyperlipoproteinemia) in particular, especially in the homozygous state, is associated with a very high incidence of premature, severe, and often generalized atherosclerosis (1). Over the past 7 years, we have studied the relationships among hyperlipoproteinemia, platelet function, soluble coagulation parameters, and clinical evidence of atherosclerosis and thrombosis. Our results suggest that patients with Type II hyperlipoproteinemia have a particular predisposition to thrombosis because of increased platelet function, both in comparison with normal subjects, and with patients with other forms of hyperlipoproteinemia. Laboratory studies suggest that these differences may be mediated through alterations in platelet fatty acid metabolism in hypercholesterolemia, particularly in thromboxane formation from arachidonate. In this paper, we shall review our data on platelet function in hyperlipoproteinemia.

Penetration of fluorescent homologous serum proteins into the wall of the aorta in rats with acute angiotensin hypertension.

A few hours of acute angiotensin hypertension in rats increased the permeability of the thoracic part of the aorta for plasma components. The permeability, which was demonstrated by means of homologous circulating fluorescent serum proteins, seemed to be diffuse rather than focal. The fluorescent proteins penetrated into the whole thickness of the aortic wall, but were to a great extent deposited in the subendothelial space and the most luminal part of the tunica media. The deposition took place in the greater part of the circumference of the aortic wall. These results are in agreement with the insudative theory of atherogenesis, and the initial stage seems to be a "damming back" of some of the serum or plasma proteins for deposition in the subendothelial space and the most luminal part of the tunica media.

Pathogenetic mechanisms in atherosclerosis

Four theories of atherogenesis are briefly reviewed and criticized: the degenerative, the thrombogenic, the platelet aggregation and the insudative theory. Evidence is presented in detail to suggest that a modified form of the insudative theory (1) accounts more satisfactorily than the other theories for the known association of risk factors with atherosclerosis and (2) allows one to understand how some of the more important risk factors operate at the level of the arterial wall. It is proposed that atherosclerotic plaques, and also certain extravascular lesions broadly associated with atherosclerosis (corneal arcus, xanthomas), arise because altered endothelial permeability allows certain reactive macromolecular plasma proteins (the plasma low density and very low density lipoproteins and fibrinogen, which are normally largely confined to the circulation) to permeate endothelium and interact with charged components of the connective tissue gel of the arterial wall or other tissues. The effect of hyperlipidemia, hyper-tension, arterial disease or injury upon this process, and the manner in which these factors interact, is examined in relation to experimental findings and clinical observations.

The Pathogenesis of Atherosclerosis

This publication represents the proceedings of a symposium on atherogenesis presented before the 1971 annual meeting of the American Association of Pathologists and Bacteriologists. The editors are to be commended for their selection of topics and speakers. In most instances each of the ten chapters gives a clear and concise picture of important facets of a disease that is due to a combination of many factors. The material presented is well documented throughout; there is a total of 959 references in the book. The introductory chapter by Haust and More is outstanding and fervently urges all investigators to abandon their unitarian theories of atherogenesis and accept a multifaceted theory of pathogenesis. Almost one third of the book, written by Stamler and co-workers, is devoted to risk factors in atherogenesis. Much of this chapter has appeared in other publications. However, Stamler and co-workers have again presented a forceful and convincing case

The precise localisation of atheroma and its association with stasis at the origin of the internal carotid artery--a radiographic investigation.

Abstract This paper presents evidence which indicates that atheroma develops in the internal carotid artery origin on its external wall, in the same region as that at which stasis occurs, and that the presence of atheroma is associated with intra-arterial stasis which can be demonstrated by contrast medium. There is a close coincidence between the site of intra-arterial stasis, atheroma, and a process known as “boundary-layer separation”, a process which can be demonstrated readily in model flows. It is suggested that this evidence of stasis supports the thrombogenetic theory of atherogenesis and that it offers an explanation for the relationship between atheroma and micro-embolism, which is one of its important clinical consequences.

Histological and immunofluorescent studies on the evolution of the human atheromatous plaque

Summary (1) Histological material from normal and atheromatous aortas and large arteries has been obtained from human subjects aged between 12 and 92. This material has been examined by conventional histological methods and by the technique of immunofluorescence, using antisera directed against a number of plasma proteins and against blood-platelet antigens. (2) In uncomplicated plaques, specific immunofluorescence was obtained with antisera specific for low-density lipoproteins at all stages of development of plaques. The distribution of fluorescence corresponded closely with that of extracellular sudanophile lipid dispersed diffusely in the ground substance of very early plaques (‘fatty streaks’), and with sudanophile droplets orientated along collagen and elastic fibres in later lesions. But, in many instances, no fluorescence was seen corresponding to intracellular lipid in ‘foam-cells’. (3) Some uncomplicated plaques also gave positive immunofluorescence with an anti-fibrinogen antiserum. Correspondence with material reacting to ‘fibrin’ stains was less close and no evidence was obtained of accompanying platelet antigens. (4) No specific localization of other serum proteins (albumin, γG-globulin and high-density lipoproteins) could be demonstrated in uncomplicated plaques. (5) A quite different pattern of distribution of fluorescence was found in plaques complicated by superimposed thrombosis or platelet deposition. (6) The bearing of these results on some theories of atherogenesis is examined and an alternative hypothesis proposed to inter-relate these findings and to correlate them with the various stages of development of the plaque.